Project Summary: Glioblastoma multiforme (GBM) is the most common primary brain tumor with about 8500 cases diagnosed each year in the United States. Within a time frame of 15 month virtually all patients succumb to this detrimental disease despite treatment efforts. Therefore, novel, ideally tumor specific approaches are necessary to combat these tumors. While single reagents may efficiently target other tumors, such as hematological malignancies, Glioblastoma is strikingly different since it is a tumor that is characterized by extensive heterogeneity, demanding the simultaneous inhibition of ideally several deregulated pathways. Our previous research has shown that targeting tumor mitochondria for cancer therapy causes significant anti-glioma effects, especially when used in combination therapies. In this proposal, an accomplished team of investigators will be characterizing a novel treatment concept for glioblastoma by causing tumor-cell specific cell death through induction of synthetic lethality in IDH1 mutated GBMs. In the first aim, we will dissect the most proximal effect of mutant IDH1 and 2-HG, involving tumor cell metabolism that finally renders tumors susceptible to Bcl-xL inhibition mediated apoptosis. In the second aim, we will test as to whether interference with anti- apoptotic Bcl-2 family members along with 2-HG results in an integrated stress response with an Activating Transcription Factor 4 (ATF4) mediated increase of Noxa, which in turn antagonizes Mcl-1 and primes tumor cells to apoptosis. In the third aim, we will assess as to whether the IDH1 mutations are synthetically lethal with tumor mitochondria targeting drugs and extend animal survival in disease-relevant animal models of glioma. Overall, our research may help to provide more specific and efficient treatments for patients suffering from GBM. Overall, this research may enhance our understanding about the treatment of brain tumors and may potentially allow us to formulate a novel treatment strategy for secondary glioblastoma and other gliomas.